Inflammation is a normal response to noxious or tissue injuring stimuli. Through increases in blood flow and vascular permeability, and through the migration of immunocompetent cells to the site of injury, the inflammatory response serves a vital role to protect the organism. The acute inflammatory response is both rapid in onset and intense, and itself liberates factors that can result in significant tissue injury. Appropriate modulation of the inflammatory response is therefore important since, if left unchecked, it could lead acutely to significant tissue injury or even to chronic inflammation. It has been suggested that inflammation may be self regulating. Mechanisms are known that are able to modulate the inflammatory response, and involve neural, endocrine, and immune pathways. In preliminary experiments, we have observed an inhibitory autoregulation of inflammation which appears to be activated by stimulation of C-fiber primary afferents at a site of inflammation. In this proposal we describe investigations to evaluate whether specific neural/endocrine pathways are involved in this autoregulation of inflammation. We will investigate the role(s) of hypothalamic-pituitary- adrenal, sympathoadrenal and postganglionic sympathetic pathways since each is known to be activated by C-fiber activity and also known to be able to modulate inflammation. The contribution of mediators released by these pathways will also be specifically evaluated. In the proposed experiments we separate the afferent and efferent arms of the hypothesized feedback pathways to dissect the mechanisms involved. Autoregulation is activated by a stimulus at one site, than the inhibitory effect is evaluated at a distant site by measuring stimulated components of the inflammatory response (i.e., plasma extravasation, blood flow nd neutrophil attraction). Finally, we will evaluate whether the feedback inhibition of inflammation occurs in the skin as well as in synovium. We will evaluate actions of the mechanisms elucidated to show that an autoregulation acts back on a single site of inflammation. The information gained from the proposed experiments will add to our understanding of the acute inflammatory response and provide a framework for investigation of other autoregulatory phenomena that may be active in inflammation. The data may also provide information relevant to human diseases characterized by either exaggerated or incomplete responses to stimuli that activate the inflammatory response and also to conditions with sustained nociceptor activity.